Peripheral neuropathy generally refers to a disorder that affects the peripheral nerves, most often manifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction. Peripheral neuropathies can be genetically acquired, can be induced by a toxic agent, or can result from peripheral ischemia or from a systemic disease. Genetically-acquired peripheral neuropathies include Refsum's disease, Abetalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodystrophy, Fabry's disease, Dejerine-Sottas syndrome, Charcot-Marie Tooth Disease (also known as Peroneal Muscular Atrophy, or Hereditary Motor Sensory Neuropathy) and others. Exemplary toxic agents which cause neurotoxicities include therapeutic drugs such as antineoplastic agents, contaminants in foods, and environmental and industrial pollutants. Ischemic peripheral neuropathies include, but are not limited to, diabetic polyneuropathy. Peripheral neuropathies associated with a systemic condition include uremia and alcoholic polyneuropathy among other disorders.
Ischemic peripheral neuropathy, particularly when it develops in the absence of diabetes, has received limited study, despite the fact that it may be a prominent feature of patients with peripheral vascular disease. Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. Typically, symptoms are dominated by sensory defects. (Tomlinson DR, et al. Diabetes 1997;46:S43–S49). The ultimate consequence of such sensory deficits involving the lower extremities may be foot ulceration initiated by traumatic injury that is inapparent to the patient. Indeed, it has been reported that 20% of all hospital admissions among diabetic patients in the United States are for foot problems. (Reiber G E, et al., in Harris M I, et al, (eds): Diabetes in America. Washington, National Institute of Diabetes and Digestive and Kidney Diseases, 1995, pp 409–427). That such ulcerations may lead to lower extremity amputation (Parkhouse N, et al., N Engl J Med 1988;318:1306–1309) is borne out by the fact that the rate of lower limb amputation is fifteen times higher in diabetic versus non-diabetic patients (Veves A, et al., Diabetes 1998;47:457–463). Even with intensive insulin therapy, as reported in the Diabetes Control and Complications Trial (DCCT), the incidence of new clinically detected neuropathy per patient per year was 3.1% in the non-retinopathy group and 7.0% in the group with baseline retinopathy; with conventional therapy, the incidence of neuropathy increased to 9.8% and 16.1% with and without retinopathy (The Diabetes Control and Complications Trial Research Group, N Engl J Med 1993;329:977–988). When loss of sensation is compounded by loss of control over blood flow due to autonomic neuropathy and lower extremity vascular obstruction, the threat of limb loss is exacerbated. In the case of peripheral artery disease, hospital mortality, length of hospitalization, and complications resulting from surgery are all increased in the presence of diabetes (Currie C J, et al., Diabetes Care 1998;21:42–48).
In view of the foregoing, a need still exists to better understand the molecular processes underlying peripheral neuropathy, and to develop improved drug therapies to replace or supplement the existing methods for treating peripheral neuropathies, particularly ischemic peripheral neuropathy. Preferably, such drug therapies would be designed to reduce or prevent nerve damage at its earliest stages and to enhance peripheral nerve repair following diagnosis and treatment.